Biofilm heterogeneity-adaptive photoredox catalysis enables red light-triggered nitric oxide release for combating drug-resistant infections

The formation of biofilms is closely associated with persistent and chronic infections, and physiological heterogeneity such as pH and oxygen gradients renders biofilms highly resistant to conventional antibiotics. To date, effectively treating biofilm infections remains a significant challenge. Herein, we report the fabrication of micellar nanoparticles adapted to heterogeneous biofilm microenvironments, enabling nitric oxide (NO) release through two distinct photoredox catalysis mechanisms. The key design feature involves the use of tertiary amine (TA) moieties, which function as sacrificial agents to avoid the quenching of photocatalysts under normoxic and neutral pH conditions and proton acceptors at acidic pH to allow deep biofilm penetration. This biofilm-adaptive NO-releasing platform shows excellent antibiofilm activity against ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilms both in vitro and in a mouse skin infection model, providing a strategy for combating biofilm heterogeneity and biofilm-related infections.


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Jinming Hu, Shiyong Liu, Chen Zhu Nov 9, 9, 2023 1H 1H and 13C NMR spectra were taken on on a 400 MHz Bruker nuclear magnetic resonance (NMR) spectrometer.Deuterated chloroform (CDCl3) and dimethylsulfoxide (DMSO-d6) were used as as solvents.High-resolution electrospray ionization mass spectrometry (HR-ESI-MS) spectra were performed on on Waters XEVO® G2-XS-TOF Mass Spectrometer equipped with an an electrospray interface.High-performance liquid chromatography (HPLC) analysis was performed with a Shimadzu HPLC system, equipped with an an LC-20AP binary pump, an an SPD-20A UV-vis detector, and a Symmetry C18 column.UV-vis absorption spectra were acquired on on a UV-3600i Plus UV-vis spectrophotometer (Shimadzu).Molecular weights and molecular weight distributions were determined by by size exclusion chromatography (SEC) equipped with Waters 1515 pump and Waters 2414 differential refractive index detector (set at at 30 30 °C).It It used a series of of two linear Styragel columns (HR2 and HR4) at at an an oven temperature of of 45 45 °C.The eluent was THF at at a flow rate of of 1.0 mL/min.Narrowly dispersed polystyrenes were employed as as the standards for calibration.Transmission electron microscopy (TEM) was conducted on on a JEOL 2010 electron microscope at at an an acceleration voltage of of 200 kV.Scanning electron microscopy (SEM) was conducted on on a Zeiss Gemini 500 field emission scanning electron microscope at at an an acceleration voltage of of 3 kV.Dynamic light scattering (DLS) and zeta potential measurements were conducted on on a Zetasizer Nano ZS ZS (Malvern).Electron paramagnetic resonance (EPR) spectra were recorded on on a JEOL JES FA200 ESR spectrometer (300 K, K, 9.063 GHz, Xband) at at room temperature.It It used the following parameters, microwave power: 1 mW; modulation frequency: 100 kHz; and modulation amplitude: 0.35 mT.Hematoxylin and Eosin (H&E), Masson staining, CD31, and TNF-! staining images were obtained on on an an IX71 fluorescence microscope (Olympus, Japan).Confocal laser scanning microscopy (CLSM) images were acquired using a Leica TCS SP5 microscope.
The wound area and quantitative comparison of of the relative intensities of of collagen, CD31, and TNF-! was carried out using image J Fiji.Data process was conducted using Origin 2021 and Graph Pad prism 8.0.All the density-functional theory (DFT) calculations were performed at at the level of of B3LYP/6-31G+(d, p) p) (LANL2DZ on on Pd) in in IEFPCM-DMSO solvent using the Gaussian 09 09 software package.

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The RNA-Seq data generated in this study have been deposited in the NCBI Gene Expression Omnibus database under the accession code GSE246965.The experimental data generated in this study are available within the Article and Supplementary Information.Source data are provided with this paper.All other data are available from the corresponding authors upon request.
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The sample size were determined as per the pilot study or previous experimental experience and standard protocols.
No data were excluded.
All replication attempts were successful and observed marked expression patterns were consistent with previously known results.Each experiments was carried out at least three independent replications and was described in the figure legend with similar results.
BALB/c mice were randomly distributed into each subgroup.
The technicians were blinded to tissues group during data collection and analyses.